Oxygen is a fundamental regulator of cellular bioenergetics and intermediary metabolism. Observing tissue oxygen level, however, has faced many hurdles. Extant techniques confront major obstacles in sampling intracellular oxygenation in a localized tissue region. Consequently a key question cannot be posed: Is the accepted view of the interaction between oxygen level and the regulation of bioenergetics, derived from model studies, also accurate in vivo? NMR offers a unique opportunity to answer such questions in vivo. Our preliminary data have demonstrated the 1H NMR visibility of the myoglobin proximal histidyl F8 NH and Val Ell methyl groups in heart muscle. These signals directly reflect intracellular oxygenation, in contrast to the commonly used 31P peaks, which monitor only the cellular interaction. We propose then to establish firmly the 1H NMR techniques to observe oxygen tension in specific tissue regions in vivo. Clearly the capacity to measure tissue oxygen opens many applications with both physiological and pathophysiological perspectives.